The focus of the laboratory work this year has been on multidrug resistance, evaluating mechanisms of reversal, determining expression in human tumor samples, and performing functional studies in both in vitro model systems and in patient samples. The studies evaluating mechanisms of multidrug resistance reversal include principally two approaches. One, we have studied the effect of protein kinase C modulation on P-glycoprotein phosphorylation and function, demonstrating that inhibition of PKC results in dephosphorylation of Pgp and decreased transport of certain agents. Second, we have continued studies of the effect of 8-Cl-cAMP on multidrug resistant breast cancer cells, with the intent of discovering the mechanism underlying the decreased expression of mdr-l/Pgp after treatment. Concurrently, studies in growth factor biology in drug resistant cells have been initiated. Finally, a Phase I clinical study of PSC 833, a new P-glycoprotein antagonist, has received IRB approval and should enroll its first patient by September 1, 1992.